Although over half of all lung cancer patients receive radiation therapy as part of their treatment plan, the therapeutic window of radiation is quite small, and it is difficult to deliver tumoricidal doses of radiation without the development of severe adverse effects in the nearby normal tissues. An agent that could protect healthy lung tissue from radiation toxicity and at the same time sensitize lung cancer tissue to radiation therapy, would be a major advance in the treatment of lung cancer, the leading cause of cancer deaths in the United States. The long term goal for this research is to develop clinically-useful, natural product-based agents that improve treatment for cancer. The objective for this application is to establish the dual action of a natural product as both a tumor cell radiosensitizr and a normal cell radioprotector by determining its mechanisms of action and therapeutic efficacy in lung cancer radiotherapy. The central hypothesis is that the natural product PPLGM sensitizes tumor cells to radiation-induced cell death through inhibition of HIF2a and induction of ROS, and protects healthy cells from radiation by enhancing their antioxidant response. To test the central hypothesis, two Specific Aims are proposed: 1) Establish the mechanisms for PPLGM-induced lung cancer cell radiosensitization and healthy lung cell radioprotection in vitro; and 2) Evaluate the therapeutic efficacy of PPLGM for lung cancer radiosensitization and healthy lung cell radioprotection in vivo. For the first aim, functional assays will be performed t identify the lung cancer cell genotypes for which PPLGM is a radiosensitizer and the healthy lung cell types for which PPLGM is a radioprotector. Mechanistic studies will be done to evaluate the involvement of HIF2a in PPLGM-induced ROS, DNA damage, and cell death for lung cancer cells, as well as transcriptional targets of the hypoxic and antioxidant responses in lung cancer and healthy lung cells. For the second aim, the radiosensitizing effects of PPLGM on lung tumors will be established in a mouse model. Additionally, the radioprotective role of PPLGM will be evaluated in a mouse model of thoracic radiation-induced pneumonopathy both short-term (1 month) and long-term (4 months). The approach is innovative because it uses a novel dietary agent that shows potent anti-cancer effects with protective effects in healthy tissues for the first time in the context of lung radiotherapy. The proposed research is significan because it is expected to advance the field of radiation therapy by development of a more effective treatment for lung cancer. The results from this project are also expected to expand understanding of how natural products act as radiosensitizers for cancer cells and, at the same time, radioprotectors for healthy cells. Such knowledge has the potential to change the field of radiation therapy and result in more effective treatment for many cancers.